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- PDB-7toq: Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptid... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7toq | |||||||||||||||
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Title | Mammalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein poly-PR | |||||||||||||||
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![]() | RIBOSOME / ribosomal binding peptide / ALS/FTD-associated dipeptide repeat protein | |||||||||||||||
Function / homology | ![]() regulation of G1 to G0 transition / exit from mitosis / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / optic nerve development / mammalian oogenesis stage / retinal ganglion cell axon guidance / G1 to G0 transition ...regulation of G1 to G0 transition / exit from mitosis / positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / regulation of translation involved in cellular response to UV / protein-DNA complex disassembly / positive regulation of DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / optic nerve development / mammalian oogenesis stage / retinal ganglion cell axon guidance / G1 to G0 transition / activation-induced cell death of T cells / positive regulation of signal transduction by p53 class mediator / ubiquitin ligase inhibitor activity / phagocytic cup / endonucleolytic cleavage to generate mature 3'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / TOR signaling / T cell proliferation involved in immune response / ribosomal small subunit export from nucleus / erythrocyte development / translation regulator activity / cellular response to actinomycin D / cytosolic ribosome / rough endoplasmic reticulum / endonucleolytic cleavage in ITS1 to separate SSU-rRNA from 5.8S rRNA and LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / gastrulation / MDM2/MDM4 family protein binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / negative regulation of ubiquitin-dependent protein catabolic process / class I DNA-(apurinic or apyrimidinic site) endonuclease activity / DNA-(apurinic or apyrimidinic site) lyase / rescue of stalled ribosome / 90S preribosome / maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / maturation of LSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / ribosomal large subunit biogenesis / maturation of SSU-rRNA / positive regulation of translation / small-subunit processome / positive regulation of apoptotic signaling pathway / protein kinase C binding / positive regulation of protein-containing complex assembly / placenta development / cellular response to gamma radiation / mRNA 5'-UTR binding / transcription coactivator binding / modification-dependent protein catabolic process / cytoplasmic ribonucleoprotein granule / spindle / G1/S transition of mitotic cell cycle / rRNA processing / protein tag activity / rhythmic process / positive regulation of canonical Wnt signaling pathway / ribosome binding / glucose homeostasis / retina development in camera-type eye / regulation of translation / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / small ribosomal subunit rRNA binding / cell body / T cell differentiation in thymus / 5S rRNA binding / large ribosomal subunit rRNA binding / perikaryon / cytosolic small ribosomal subunit / cytosolic large ribosomal subunit / mitochondrial inner membrane / tRNA binding / cytoplasmic translation / postsynaptic density / cell differentiation / protein stabilization / rRNA binding / ribosome / protein ubiquitination / structural constituent of ribosome / ribonucleoprotein complex / cell cycle / translation / positive regulation of protein phosphorylation / positive regulation of apoptotic process / cell division / DNA repair / mRNA binding / apoptotic process / ubiquitin protein ligase binding / synapse / dendrite / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / protein kinase binding / perinuclear region of cytoplasm / Golgi apparatus / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / DNA binding Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() ![]() ![]() | |||||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||||||||
![]() | Loveland, A.B. / Svidritskiy, E. / Susorov, D. / Lee, S. / Park, A. / Zvornicanin, S. / Demo, G. / Gao, F.B. / Korostelev, A.A. | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Ribosome inhibition by C9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM. Authors: Anna B Loveland / Egor Svidritskiy / Denis Susorov / Soojin Lee / Alexander Park / Sarah Zvornicanin / Gabriel Demo / Fen-Biao Gao / Andrei A Korostelev / ![]() ![]() Abstract: Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ...Toxic dipeptide-repeat (DPR) proteins are produced from expanded GC repeats in the C9ORF72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥20 repeats inhibit the ribosome's peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryogenic electron microscopy (cryo-EM) reveals that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center (PTC). Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with poly-PR and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD. | |||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 4.7 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.9 MB | Display | ![]() |
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Full document | ![]() | 1.9 MB | Display | |
Data in XML | ![]() | 332.9 KB | Display | |
Data in CIF | ![]() | 585.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 26035MC ![]() 7tooC ![]() 7topC ![]() 7torC ![]() 7tosC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-RNA chain , 6 types, 6 molecules A18SA25SA58SA5SMRNAPTRN
#1: RNA chain | Mass: 548024.188 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#2: RNA chain | Mass: 1182428.000 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#3: RNA chain | Mass: 50143.648 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#4: RNA chain | Mass: 38691.914 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#82: RNA chain | Mass: 3097.885 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() ![]() |
#84: RNA chain | Mass: 24802.785 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
+Protein , 21 types, 21 molecules AL02AL07AL08AL13AL16AL18AL20AL22AL25AL29AL30AL38AL40AL42ARACAS00AS07AS16AS19AS21AS26
+60S ribosomal protein ... , 25 types, 25 molecules AL03AL04AL05AL06AL09AL11AL12AL14AL15AL17AL19AL21AL23AL26AL27AL28AL31AL32AL33AL34AL35AL36AL37AL43EL28
-Ribosomal protein ... , 3 types, 3 molecules AL10AL24AS05
#13: Protein | Mass: 24511.861 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#27: Protein | Mass: 7512.774 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#54: Protein | Mass: 21525.941 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Protein/peptide , 4 types, 4 molecules AL39AL41ALP0PR
#42: Protein/peptide | Mass: 6295.562 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#44: Protein/peptide | Mass: 3213.075 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#47: Protein/peptide | Mass: 3298.991 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#83: Protein/peptide | Mass: 5104.186 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) ![]() |
+40S ribosomal protein ... , 25 types, 25 molecules AS01AS02AS03AS04AS06AS08AS09AS10AS11AS12AS13AS14AS15AS17AS18AS20AS22AS23AS24AS25AS27AS28AS29AS30AS31
-Non-polymers , 1 types, 4 molecules ![](data/chem/img/ZN.gif)
#85: Chemical | ChemComp-ZN / |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Mamalian 80S ribosome bound with the ALS/FTD-associated dipeptide repeat protein PR20 Type: RIBOSOME / Entity ID: #1-#84 / Source: MULTIPLE SOURCES | ||||||||||||||||||||
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Molecular weight | Value: 4 MDa / Experimental value: NO | ||||||||||||||||||||
Source (natural) |
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Buffer solution | pH: 7 | ||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Humidity: 95 % |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 500 nm |
Image recording | Electron dose: 30 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
EM software | Name: FREALIGN / Version: 9.11 / Category: 3D reconstruction |
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CTF correction | Type: PHASE FLIPPING ONLY |
3D reconstruction | Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 63475 / Symmetry type: POINT |